A great deal of research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and ARC in humans is increasing at an alarming rate. The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired by the infection, suffer from numerous opportunistic infections including Kaposi's sarcoma and Pneumocystis carinii pneumonia. No cure for AIDS is known and current treatments are largely without adequate proof of efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having or suspected of having the disease.
Retroviruses are a class of ribonucleic acid (RNA) viruses that replicate by using reverse transcriptase to form a strand of complementary DNA (CDNA) from which a double stranded, proviral DNA is produced. This proviral DNA is then randomly incorporated into the chromosomal DNA of the host cell making possible viral replication by later translation of the integrated DNA containing the viral genome.
Many of the known retroviruses are oncogenic or tumor causing. Indeed the first two human retroviruses discovered, denoted human T-cell leukemia virus I and II or HTLV-I and II, were found to cause rare leukemias in humans after infection of T-lymphocytes. The third such human virus to be discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes and has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC).
The envelope protein of HIV is a 160 kDa glycoprotein. The protein is cleaved by a protease to give a 120 kDa external protein, gp 120, and a transmembrane glycoprotein, gp 41. The gp 120 protein contains the amino acid sequence that recognizes the receptor on CD4-positive human T-helper cells. Recently it was reported that the polysulfated polysaccharides dextran sulfate, carrageenans of sea algae, pentosan polysulfate, and heparin are highly specific inhibitors of HIV-1 replication in vitro. M. Ito, et al., (1987) Antiviral. Res. 7, 361-367. Baba et al., Antiviral Res. 9, 335-343 (1988). O. Yoshida (1988) Biochem. Pharmacol. 37, 2887-2981. R. Ueno and S. Kuno, (1987) Lancet i, 1379. The mechanism of this activity has been studied by Baba et al., (1988) Proc. Natl. Acad. Sci. USA, 85, 6132-6136. Another recent report indicates that antisera prepared against synthetic peptides corresponding to amino acid residues 307-330 and 303-321 in gp 120 inhibit HIV-induced syncytium formation. Rusche et al., Proc. Natl. Acad. Sci. USA 85, 2898-3202 (1988) and Palker et al., Proc. Natl. Acad. Sci USA 85, 1932-1936 (1988). Antibody binding to residues 303-330 in HIV gp 120 apparently interferes with the binding of the virus to the CD4 receptor and fusion with the plasma membrane.
Applicants have discovered that fractions of sulfated polysaccharides such as heparin, dextran sulfate and pentosan polysulfate, designated anti-HIV Heparin, anti-HIV dextran sulfate and anti-HIV-pentosan polysulfate, respectively, can be obtained by binding to a peptide corresponding to residues 301-324 of the HIV gp 120 protein and that anti-HIV Heparin, anti-HIV dextran sulfate, and anti-HIV pentosan polysulfate have significantly higher potency than unfractionated sulfated polysaccharides to prevent syncytium formation and appearance of viral P24 core antigen in the culture medium of HIV-infected CD4 cells and significantly reduces HIV infectivity. Anti-HIV sulfated polysaccharides can be used in the treatment of AIDS and ARC. The gp 120 peptide fragment is used in standard affinity chromatography to isolate anti-HIV sulfated polysaccharides.